Drug Interactions between gefitinib and ivacaftor / lumacaftor

ADJUST DOSE: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of gefitinib, which is primarily metabolized by the isoenzyme. When a single 500 mg dose of gefitinib was administered following pretreatment with the potent CYP450 3A4 inducer rifampin (600 mg once daily for 16 days) in healthy male volunteers, mean gefitinib systemic exposure (AUC) decreased by 83% compared to administration of gefitinib alone. Reduced efficacy of gefitinib may occur.

MANAGEMENT: When used concomitantly with potent CYP450 3A4 inducers, the manufacturer recommends increasing the dosage of gefitinib to 500 mg daily in the absence of severe adverse reactions. The normal recommended dosage of 250 mg once daily may be resumed 7 days after discontinuing the CYP450 3A4 inducer.

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MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of gefitinib, which is primarily metabolized by the isoenzyme. According to the product labeling, administration of gefitinib (250 mg single dose) with the potent inhibitor itraconazole (200 mg once a day for 12 days) increased the mean gefitinib systemic exposure (AUC) by 88% in healthy male volunteers. This increase may be clinically significant, as adverse events of gefitinib are related to dose and exposure.

MANAGEMENT: Caution is advised if gefitinib is administered with CYP450 3A4 inhibitors, particularly potent ones like itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, conivaptan, idelalisib, nefazodone, cobicistat, delavirdine, and most protease inhibitors. Pharmacologic response to gefitinib should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the dosage adjusted as necessary. Patients should be advised to contact their physician if they experience possible symptoms of gefitinib toxicity such as severe diarrhea, nausea, dyspnea, cough, and fever.

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